This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Histone deacetylases (HDACs) are zinc-dependent hydrolytic enzymes involved in chromatin remodeling and play a critical role in the regulation of gene transcription via deacetylation of histone lysine residues. The small molecule HDAC inhibitor (HDI), suberoylanilide hydroxamic acid (SAHA;also known as Zolinza or Vorinostat) is currently in many clinical trials for cancer chemotherapy and holds great promise for the amelioration of other diseases as well. However, SAHA and other HDIs in development have molecular functionality and broad-spectrum activity with known pharmacokinetic difficulties and will certainly be problematic in the treatment of chronic illnesses. This research will develop new classes of HDIs and offer novel strategies for HDAC inhibition. Key to this project is the design of isozyme-specific HDIs based on competent models of the enzyme. Missing from current efforts in the development of HDIs is the availability of good models of the HDAC Class I isozymes from which to base drug design. This project combines both computational biochemistry and organic synthesis to achieve the goal of isozyme specificity in an HDI.